DNA is under constant assault from damaging agents that produce a complex array of lesions. Left unrepaired, these lesions have the potential to result in cell death, or may lead to mutations that alter the biology of the cell and compromise the health of the organism, leading to degenerative diseases, cancer, and death. Consequently, inter-individual variation in the ability to respond to DNA damage is a critical component in answering a central question in biology: why do some people develop disease, while others do not?
Numerous human diseases are associated with mutations in DNA repair genes, and genetic tests are now available for a subset of highly penetrant mutations. Oncologists have begun to use these tests to tailor medical treatment and prevention to individual needs, for example by recommending specific cancer screening programs to patients based on their genetic susceptibility. Despite the enormous insight that has been gained from genetic screens, robust predictions of phenotype and disease susceptibility are hindered by epigenetic complexity, tissue-specific variability in gene expression, uncharacterized mutations, and variability in lifestyle and environmental exposure. Consequently, phenotypic screens are needed to complement genetic screens.